Recent research suggests that the presence of neuropsychiatric symptoms is a risk factor for progression from mild cognitive impairment (MCI) to Alzheimer's disease (AD), and an individual's susceptibility to distress significantly increases their risk of AD. These findings imply that poor resilience to behavioral stress is not simply a characteristic of dementia, but may reflect mechanisms involved in disease etiology. The increased activation of stress-related brain circuits, such as that between the basolateral amygdala (BLA) and the hippocampus, may underlie aspects of hippocampus pathology and exacerbate memory impairment in AD. However, the mechanistic link between behavioral stress, amygdala output, and hippocampal dysfunction in the normal and diseased brain remains unclear. Our preliminary results utilize optogenetic and pharmacogenetic techniques to show that activation of specific BLA afferents to the hippocampus mimics the effects of behavioral stress upon both cellular pathology and cognitive function. Importantly, silencing these pathways prevents cognitive impairment following repeated behavioral stress. Moreover, chronic inactivation of this circuit appears to ameliorate AD-like phenotypes in a mouse model of familial AD. Therefore, the BLA- hippocampus circuit, so heavily implicated in the impact of stress upon hippocampal function, should be closely evaluated, in a manner only achievable via the use of cell- and circuit-specific optogenetic techniques, for its contribution to cognitive dysfunction and cellular pathology in AD. Our preliminary data also show that the BLA- hippocampal stress circuit is not comprised of a solitary pathway, but that the ventral and dorsal components of this circuit may play differential roles in the modulation of anxiety and the impact of behavioral stress upon cognitive function. This application will test the hypothesis that the activation of BLA input pathways to the HPC as a result of behavioral stress leads to the exacerbation of AD pathology, and will determine the relative contribution of the ventral and dorsal components of this pathway. These studies will examine how the targeted silencing of specific brain circuits can slow disease progress and ameliorate cognitive impairment, and may provide rationale for the application of deep brain stimulation techniques in the treatment of AD.